Description: Caffeine is a naturally occurring xanthine derivative used as a CNS and respiratory stimulant, or as a mild diuretic. Other xanthine derivatives include the bronchodilator theophylline and theobromine, a compound found in cocoa and chocolate.

Caffeine is found in many beverages and soft drinks. Caffeine is often combined with analgesics or with ergot alkaloids for the treatment of migraine and other types of headache. Caffeine is also sold without a prescription in products marketed to treat drowsiness. Caffeine was first approved by the FDA for use in a drug product in 1938.

Clinically, it is used both orally and parenterally as a respiratory stimulant. Caffeine reduces the frequency of apneic episodes by 30—50% within 24 hours of administration. A commercial preparation of parenteral caffeine, Cafcit®, was FDA approved for the treatment of apnea of prematurity in October 1999, after years of availability only under orphan drug status (e.g., Neocaf®). The FDA has continued the orphan drug status of the approved prescription formulation.

Mechanism of Action: Caffeine is a mild, direct stimulant at all levels of the CNS and also stimulates the heart and cardiovascular system. The related xanthine, theophylline, shares these properties and is widely used in the treatment of pulmonary disease. Both caffeine and theophylline are CNS stimulants, with theophylline exerting more dramatic effects than caffeine at higher concentrations. Caffeine also stimulates the medullary respiratory center and relaxes bronchial smooth muscle. Caffeine stimulates voluntary muscle and gastric acid secretion, increases renal blood flow, and is a mild diuretic.

While the clinical responses to caffeine are well known, the cellular mechanism of action is uncertain. Several theories have been proposed. At high concentrations, caffeine interferes with the uptake and storage of calcium by sarcoplasmic reticulum of striated muscle. While this action would explain the effects of caffeine on cardiac and skeletal muscle, it does not appear to occur at clinically achievable concentrations. Inhibition of phosphodiesterases (and subsequent accumulation of cyclic nucleotides) also does not appear to occur at clinically achievable concentrations. Currently, it is believed that xanthines act as adenosine-receptor antagonists. Adenosine acts as an autocoid, and virtually every cell contains adenosine receptors within the plasma membrane. Adenosine exerts complex actions. It inhibits the release of neurotransmitters from presynaptic sites but works in concert with norepinephrine or angiotensin to augment their actions. Antagonism of adenosine receptors by caffeine would appear to promote neurotransmitter release, thus explaining the stimulatory effects of caffeine.

Recently, a distinct syndrome has been associated with caffeine withdrawal. It is possible that the manifestations of caffeine withdrawal may be secondary to catecholamine or neurotransmitter depletion. Withdrawal symptoms are severe, and include headache, vomiting, nausea, hallucination and temporary psychological disorder.

The following mechanisms of action are hypothesized for caffeine's action in apnea of prematurity: 1) stimulation of the respiratory center, 2) increased minute ventilation, 3) decreased threshold to hypercapnia, 4) increased response to hypercapnia, 5) increased skeletal muscle tone, 6) decreased diaphragmatic fatigue, 7) increased metabolic rate, and 8) increased oxygen consumption. All of these actions are thought to be related to adenosine receptor antagonism.

Pharmacokinetics: Caffeine is administered orally and intravenously. Caffeine and citrated caffeine are well absorbed from the GI tract. Absorption from suppositories may be slow and erratic. Following oral administration, peak plasma concentrations in adults are reached within 50—75 minutes; in neonates oral administration of caffeine results in peak concentrations in 0.5—2 hours. Formula feedings do not affect the time to maximum concentrations after oral dosing. Therapeutic caffeine concentrations are reported to be 5—25 mg/L in adults. Therapeutic plasma concentrations of caffeine for the treatment of neonatal apnea of prematurity are roughly 13—25 mg/L, however, concentrations of 26—40 mg/L may be needed for some infants to obtain a reduction in apneic episodes.[2070] Caffeine is distributed rapidly to all body tissues and readily crosses the blood-brain and placental barriers. Caffeine is roughly 36% bound to plasma proteins. In adults, caffeine is partially metabolized in the liver via demethylation reactions dependent on the CYP-450 1A2 isoenzyme; major metabolites include paraxanthine (80%), theobromine (10%) and theophylline (4%). In neonates, it is interesting to note that interconversion from theophylline to caffeine has been noted. Unchanged caffeine and its metabolites are excreted in the urine. Plasma half-life is 3—7 hours in adults.